The development of spontaneous autoimmune disease in mice and other species has been shown to be partly determined by genetic factors. In previous studies we have shown that two genes carried by NZB mice are particularly involved, and that related NZ strains carry only one of these genes. The NZB strain is also defective in its ability to be tolerated by heterologous serum proteins, and is also susceptible to the induction of plasmacytomas by mineral oil. We have also shown that genetically controlled factors determine elevated endogenous stem cell numbers, and hyporesponsiveness in vitro to erythrocyte antigens in both the NZB and NZC mice. The strain NZW does not express these immunological abnormalities, but may carry genes involved in the resistance to tolerance, and anti-DNA antibody production. The present studies principally involve a genetic analysis of these various abnormal traits, and will attempt to determine the cellular level of gene action. The genetic questions are: (1) Are all or many of these abnormal traits linked to one another or even involve a common gene? (2) Are any of these genes linked to, or a part of, other immune response gene systems? (3) In particular, is the susceptibility to plasmacytoma induction shown by both BALB/c and NZB mice, an expression of an autoimmune mechanism? The cellular studies, in turn, seek to determine which cell types are involved in expressing the particular gene defined in these systems, principally, the model systems of tolerance and in vitro hyporesponsiveness.